This invention relates to crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxy butanedioate (1:1) salts having the formula shown below: 
The invention further relates to a method of making 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxybutanedioate (1:1) salts. The compounds of the present invention are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals, especially humans. The invention further relates to pharmaceutical compositions containing such compounds.
The free base, 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, is described in co-pending U.S. Ser. No. 09/383,755, filed Aug. 26, 1999, the disclosure of which is hereby incorporated herein by reference in its entirety. The foregoing application is assigned in common with the present application. The aforementioned free base is useful in the treatment of hyperproliferative diseases such as cancers.
The present invention relates to crystalline tartrate salts of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one having the formula shown below: 
Two crystal forms of formula I have been identified. The crystal forms of formula I are herein referred to as crystal form A and crystal form B. Crystal form A is an anhydrous crystalline salt of formula 1, while crystal form B is a sesquihydrate crystalline salt of formula 1.
The present invention relates to 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxy butanedioate salts. The 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl))-1-methyl-1H-quinolin-2-one has a chiral center at the 6-postion. Thus, the free base, 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinol in-2-one, may have specific rotations of (+) or (xe2x88x92). The tartrate salt may be L-tartaric acid or D-tartaric acid. L-tartaric acid is also known as (2R,3R)-(+)-tartaric acid, while D-tartaric acid is (2S,3S)-(xe2x88x92)-tartaric acid. Both acids are available from Aldrich Chemical Company, Inc., Milwaukee, Wis.
Particularly preferred salts include (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxy butanedioate salt and (xe2x88x92)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxy butanedioate salt. Other particularly preferred salts include 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (xe2x88x92)-2,3-dihydroxy butanedioate salt and 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxy butanedioate salt.
More particularly preferred salts include (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (xe2x88x92)-2,3-dihydroxy butanedioate salt and (xe2x88x92)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxy butanedioate salt. The salts of the present invention may be present in anhydrous or hydrous form.
The present invention further relates to (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxy butanedioate salt. The invention also relates to (xe2x88x92)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (xe2x88x92)-2,3-dihydroxy butanedioate salt.
The present invention further comprises pharmaceutical compositions of crystal forms A and B of the compound of formula I and a method for the production of crystal forms A and B of the compound of formula I.
It is a further object of the present invention to provide crystal forms A and B in a pharmaceutically orally administered composition. Crystal forms A and B of the compound of formula I are useful for the oral administration of the drug in solid form, such as tablets. Crystal form A is preferred for use in the preparation of pharmaceutical compositions containing the compound of formula I in tablet form for oral administration.
Crystal forms A and B have been characterized by powder X-ray diffractometry. The anhydrous crystal form of the present invention is identified in this application as crystal form A. The second crystal form of formula I is a sesquihydrate having approximately 5.5% water and is identified herein as crystal form B.
The anhydrous crystal form A of (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (xe2x88x92)-2,3-dihydroxy butanedioate is characterized by high-intensity diffraction peaks at diffraction angles (2xcex8) of about 3.6, 17.2, 17.6, 18.8, 19.2, 20.4 and 22.1 in a powder X-ray diffraction pattern. The experimental conditions under which the powder X-ray diffraction was conducted are as follows: Cu anode; wavelength 1: 1.54056; wavelength 2: 1.54439 (Rel Intensity: 0.500); range #1-coupled: 3.000 to 40.000; step size: 0.040; step time: 1.00; smoothing width: 0.300; and threshold: 1.0. The characteristic diffraction peaks at diffraction angles (2xcex8) in a powder X-ray diffraction analysis for the crystal form A are shown in Table 1.
The hydrate crystal form B of (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4(3-ethynyl-phenyl)-1-methyl-1-H-quinolin-2-one, (xe2x88x92)-2,3-dihydroxy butanedioate is characterized in that the crystal provides high-intensity diffraction peaks at diffraction angles (2xcex8) of about 5.1, 8.1, 18.2, 18.8, 20.2, 20.8, 23.6, 25.8 and 26.0 in a powder X-ray diffraction pattern. The experimental conditions under which the powder X-ray diffraction was conducted are as follows: Cu anode; wavelength 1: 1.54056; wavelength 2: 1.54439 (Rel Intensity: 0.500); range #1-coupled: 3.000 to 40.000; step size: 0.040; step time: 1.00; smoothing width: 0.300; and threshold: 1.0. The characteristic diffraction peaks at diffraction angles (2xcex8) in a powder X-ray diffraction analysis for crystal form B are shown in Table 2.
The characteristic d-spacings, intensities, and 2-theta (2xcex8) values for the diffraction pattern of crystal forms A and B are shown below in Tables 1 and 2, respectively.
It is to be understood that the powder X-ray diffraction pattern is only one of many ways to characterize the arrangement of atoms comprising 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, 2,3-dihydroxy butanedioate and that other methods well known in the art, e.g. single crystal X-ray diffraction, Near Infrared Spectroscopy, etc. may be used to identify crystal forms A and B.
The present invention relates to a compound which is crystal form A of the compound (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (xe2x88x92)-2,3-dihydroxy butanedioate or (xe2x88x92)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxy butanedioate that exhibits a powder X-ray diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 3.6, 6.2, 7.2, 9.5, 10.8, 17.2, 17.6, 19.2, and 22.1. This invention also relates to a crystal of (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (xe2x88x92)-2,3-dihydroxy butanedioate or (xe2x88x92)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxy butanedioate that exhibits a powder X-ray diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately the values shown in Table 1 above.
The present invention relates to a compound which is crystal form B of the compound (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (xe2x88x92)-2,3-dihydroxy butanedioate or (xe2x88x92)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxy butanedioate that exhibits a powder X-ray diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 5.1, 8.1, 16.4, 18.2, 20.8, 21.4, 21.7, 24.4, 30.2, 32.1, 36.8 and 37.4. This invention also relates to a crystal of (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (xe2x88x92)-2,3-dihydroxy butanedioate or (xe2x88x92)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one, (+)-2,3-dihydroxy butanedioate that exhibits a powder X-ray diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately the values shown in Table 2 above.
The invention also relates to a process for the preparation of the compounds of the formula I. The free base of formula I is prepared according to the manner described in Example 1. The free base has one chiral carbon at the 6-position. Example 2 discloses the method and process for preparation and separation the two enantiomers of the free base, 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one. The faster eluting enantiomer A causes the plane of polarization to rotate in counterclockwise (negative) direction, i.e., (xe2x88x92) enantiomer. While, the slower moving enantiomer B causes the plane of polarization to rotate in clockwise (positive) direction, i.e., (+) enantiomer.
The tartrate salts of the compound of formula I are made by mixing desired tartaric acid (i.e., D or L) with the free base 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one. The free base may be either the (xe2x88x92) or (+) enantiomer. The reaction to form crystal form B is done in a mixed solvent system, such as THF/water. Recrystallization of the tartaric salt of formula I in an organic solvent, such as ethyl acetate, at elevated temperatures results in the isolation of crystal form A.
In one preferred embodiment crystal form B is prepared according to the method comprising the steps of (i) charging a flask with free base of the compound of formula I and a solvent; (ii) addition of the tartrate salt to the free base solution followed by stirring to form a thick slurry; and (iii) isolation of the solids by filtration followed by drying. The aforementioned method to prepare crystal form B may be modified to make crystal form A. Following formation of the thick slurry in step (ii) dry ethyl acetate is added to the reaction flask and the stirred supension is atmospherically distilled. As solvent is distilled off fresh ethyl acetate is added, followed by distillation to a small volume. The reaction mixture is then granulated at ambient temperature followed by isolation of the solids (crystal form A) using filtration and vacuum drying.
Crystal form A of the present invention can be produced from isolated crystal form B. Crystal form A is produced by the steps of (i) heating the crystalline form B in an organic solvent, such as ethyl acetate; (ii) removing the water azeotropically followed by replacement with dry ethyl acetate; (iii) removing the solvent under atmospheric conditions to isolate the solids; and (iv) washing the solids using ethyl acetate and subjecting the product to vacuum drying at elevated temperatures, e.g., 40xc2x0 C. Note that it is also possible to remove the solvent in step (iii) under vacuum.
Crystal form A of the present invention may also be prepared directly without isolation of the crystal form B. For example, crystal form A may be produced by refluxing at 80xc2x0 C.-82xc2x0 C. for 1-hour a mixture of the free base of the compound of formula I (approximately 1.3 equivalents) with the tartrate salt in hot 2B ethanol (20 volume). The mixture is allowed to cool to room temperature slowly followed by stirring overnight. The solvent is then removed under atmospheric conditions and the isolated solid is dried.
The salts of the present invention may exist in amorphous form. Although, such forms may be unstable. However, such salts may be converted to crystalline forms according to methods well known to those of ordinary skill in the art, e.g., heating, etc.
It is to be understood that the methods described herein are only exemplary and are not intended to exclude variations in the above parameters which allow the production of crystal forms A and B in varying granulations and yields, according to the desired storage, handling and manufacturing applications of the compound. Crystal forms of the present invention may be further processed, such as granulation or milling, to form microcrystalline material suitable for bulk manufacturing purposes.
The crystal forms A and B can be characterized using powder X-ray diffractometry.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, as defined above, a prodrug or solvate thereof, that is effective in inhibiting farnesyl protein transferase. In one embodiment of this method, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin""s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, as defined above, a prodrug or solvate thereof, that is effective in treating abnormal cell growth.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula I, a prodrug or solvate thereof, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
The present invention also relates to a method for the treatment of an infection in a mammal, including a human, that is facilitated by farnesyl protein transferase, such as hepatitus delta virus or malaria, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I as defined above, a prodrug or solvate thereof.
This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the formula I, as defined above, a prodrug or solvate thereof, that is effective in inhibiting farnesyl protein transferase, and a pharmaceutically acceptable carrier. In one embodiment of said composition, said abnormal cell growth is cancer, including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin""s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. In another embodiment of said pharmaceutical composition, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
This invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the formula I, as defined above, a prodrug or solvate thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier.
The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises a therapeutically effective amount of a compound of formula I, as defined above, a prodrug or solvate thereof, in combination with a pharmaceutically acceptable carrier and an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.
This invention also relates to a pharmaceutical composition for the treatment of an infection in a mammal, including a human, that is facilitated by farnesyl protein transferase, such as malaria or hepatitus delta virus, comprising an amount of a compound of the formula I, as defined above, a prodrug or solvate thereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier.
xe2x80x9cAbnormal cell growthxe2x80x9d, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs; and (4) any tumors that proliferate by virtue of farnesyl protein transferase.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, unless otherwise indicated, refers to the act of treating as xe2x80x9ctreatingxe2x80x9d is defined immediately above.